Targeting FAK and integrin signaling in preclinical models of Ewing sarcoma

 描述(申请人提供)：研究：尤文肉瘤是儿童第二常见的骨恶性肿瘤。治疗方案毒性很大，转移性疾病的患者很少能治愈。由于验证的临床靶点数量不足，对尤文肉瘤患者使用靶向治疗的努力一直受到限制。为此，我对尤文肉瘤细胞系进行了动态组分析，发现粘着斑激酶(FAK)高度活跃。我证明了激活的FAK在肿瘤中表达，下调该靶点会损害这种疾病的生长、生存和肿瘤增殖。然而，目前尚不清楚FAK在尤文肉瘤中是如何被激活的，FAK是否像在其他癌症中看到的那样是发生转移所必需的，以及如何在尤文肉瘤患者的临床上最好地利用FAK抑制剂。在最近的一次筛查工作中，我发现尤文肉瘤细胞系依赖于许多整合素，这是一类已知激活FAK并在癌症转移中发挥作用的跨膜受体。基于更多的初步数据，我现在建议证明尤文肉瘤依赖于其中一种整合素ITGB2来实现生长、存活、肿瘤进展和FAK激活。我还建议证明ITGB2和FAK在这种疾病的转移过程中是必需的。最后，在一项大规模筛选工作中，我发现Aurora激酶抑制剂与FAK抑制在尤文肉瘤细胞系中具有协同作用，以确定与FAK抑制剂一起使用的治疗组合。因此，我建议验证初步发现，Aurora B激酶抑制剂与FAK抑制剂联合使用是一种有效的组合，并可用于尤文肉瘤患者的第二代临床试验。候选人的职业目标：这一职业发展奖所涵盖的时间段将是我在向独立过渡之前职业生涯的最后一个关键培训阶段。在此期间，我将获得必要的知识、实验室技能、写作经验和成熟度，以申请儿科肿瘤学终身教职。从长远来看，我的目标是成为一名领先的专家，通过在实验室中使用创新的方法来识别儿童肉瘤的新治疗策略。本申请中提出的研究将在达纳-法伯癌症研究所的金伯利·斯特格迈尔博士和布罗德研究所的托德·戈卢布博士的指导下进行，并由癌症生物学领域的领先专家组成的科学咨询委员会提供指导。环境：达纳-法伯癌症研究所拥有国际公认的癌症生物学和翻译发现研究项目。儿科肿瘤科在培训年轻的内科科学家担任儿科癌症研究的领导角色方面有着杰出的记录。该培训的毕业生继续做出变革性的发现，继续塑造未来的儿科癌症患者的临床护理。

 DESCRIPTION (provided by applicant): Research: Ewing sarcoma is the second most common bone malignancy of childhood. Treatment regimens are highly toxic and patients with metastatic disease are rarely cured. Efforts to utilize targeted therapies for patients with Ewing sarcoma have been limited due to an insufficient number of validated clinical targets. To this end, I performed a kinome profiling screen of Ewing sarcoma cell lines that identified focal adhesion kinase (FAK) as highly active. I demonstrated that activated FAK is expressed in tumors and downregulation of this target impairs growth, survival, and tumor proliferation in this disease. However, it is currently unknown how FAK is activated in Ewing sarcoma, whether FAK is necessary for the development of metastasis as seen in other cancers, and how to best utilize FAK inhibitors in the clinic for patients with Ewing sarcoma. In a recent screening effort to identify non-kinase molecular vulnerabilities in Ewing sarcoma, I found that Ewing sarcoma cell lines are dependent on a number of integrins, a class of transmembrane receptors known to activate FAK and play a role in cancer metastasis. Based on additional preliminary data, I now propose to demonstrate that Ewing sarcoma is dependent on one of these integrins, ITGB2, for growth, survival, tumor progression, and FAK activation. I also propose to show that ITGB2 and FAK are necessary for the development of metastasis in this disease. Finally, in a large-scale screening effort to identify therapeutic combinations for use with FAK inhibitors, I found that Aurora kinase inhibitors synergized with FAK inhibition in a Ewing sarcoma cell line. Therefore, I propose to validate the preliminary finding that Aurora B kinase inhibitors in combination with FAK inhibition is an efficacious combination and a candidate for testing in second-generation clinical trials for patients with Ewing sarcoma. Candidate Career Goals: The time period encompassed by this career development award will be the final critical training phase of my career prior to transition to independence. During this time I will gain the knowledge, laboratory skills, writing experience, and maturity necessary to apply for a tenure-track physician-scientist position in academic pediatric oncology. In the long- term, my goal is to be a leading expert in the identification of new therapeutic strategies for pediatric sarcomas through the use of innovative approaches in the lab. The research proposed in this application will be performed under the mentorship of Dr. Kimberly Stegmaier at Dana- Farber Cancer Institute and Dr. Todd Golub at the Broad Institute with guidance of a scientific advisory committee composed of leading experts in cancer biology. Environment: The Dana-Farber Cancer Institute houses internationally recognized research programs in cancer biology and translational discovery. The Division of Pediatric Oncology has a distinguished record of training young physician-scientists for leadership roles in pediatric cancer research. Graduates from this training have gone on to make transformative discoveries that continue to shape the future of clinical care for pediatric cancer patients.